X-Message-Number: 30049
Date: Thu, 22 Nov 2007 08:23:30 -0800 (PST)
From: 
Subject: dimethyl isosorbide is a consistently low toxicity solvent

[Cryoprotectant toxicity is one major roadblock to success in organ
vitrification. All available comparisons indicate that substitution of
DMSO with dimethyl isosorbide in vitrification solutions would likely
reduce toxicity. However I am not aware of any actual cryopreservation
test using dimethyl isosorbide.]

PDA J Pharm Sci Technol. 2007 Mar-Apr;61(2):64-74.
Cardiovascular effects of selected water-miscible solvents for
pharmaceutical injections and embolization materials: a comparative
hemodynamic study using a sheep model.
    Laurent A, Mottu F, Chapot R, Zhang JQ, Jordan O, R fenacht DA, Doelker
E, Merland JJ. Laboratory of Neuroradiology and Therapeutic Angiography,
Lariboisi re Hospital, University of Paris, France.
    Generally, organic water-miscible solvents are used intravascularly
(both intravenously and intra-arterially) for preparing two types of
formulations, namely, pharmaceutical injections of poorly soluble drugs and
precipitating liquid embolic polymeric materials for the minimally invasive
treatment of aneurysms, arteriovenous malformations, or tumors, by arterial
route. Although several of such solvents have been used in both drug
delivery and interventional radiology, their safety profile is a concern. In
particular, there is a lack of comparative investigations of their
cardiovascular effects when injected intra-arterially. We selected 13
non-aqueous water-miscible solvents based on their capacity to solubilize
drugs or embolic polymeric materials, and on their described use, at least
diluted with water, in pharmaceutical formulations. Their in vivo
hemodynamic toxicity in male adult sheep after infra-renal aorta
catheterization has been estimated with respect to the arterial and venous
pressures, as well as the heart rate. Saline solution was used as a control.
Three different volumes (0.1, 0.5, and 1.0 mL) were infused rapidly. An
increase in arterial pressure and concomitant decrease in venous pressure,
which we considered as signs of a cardiovascular toxicity, were observed to
a differing extent for all organic solvents. Changes in heart rate were
negligible. Based on the intensity of arterial pressure change after a 1-mL
infusion, a classification of the toxicity of the solvents following
intra-arterial infusion is proposed: Solvents devoid of significant
cardiovascular toxicity: dimethyl isosorbide (DMI), Glycofurol 75,
polyethylene glycol 200 (PEG 200), diglyme. Solvents with moderate
cardiovascular toxicity: tetrahydrofurfuryl alcohol (THFA), ethanol,
acetone, Solketal, glycerol formal, dimethyl sulfoxide (DMSO). Solvents with
marked cardiovascular toxicity: propylene glycol, ethyl lactate,
N-methyl-2-pyrrolidone (NMP). Emphasis is put on the relative character of
the proposed ranking and on the lack for certain solvents, at least in the
open literature, of data pertaining at other forms of toxic effects (e.g.,
undesirable pharmacological action, carcinogenicity, teratogenicity,
mutagenicity, and irritating and sensitizing properties), all factors that
have to be considered when selecting a proper solvent.
PMID: 17479714

AJNR Am J Neuroradiol. 2006 Oct;27(9):1900-6.
Organic solvents as vehicles for precipitating liquid embolics: a
comparative angiotoxicity study with superselective injections of swine rete
mirabile.
    Dudeck O, Jordan O, Hoffmann KT, Okuducu AF, Tesmer K, Kreuzer-Nagy T,
R fenacht DA, Doelker E, Felix R. Department of Radiology, Charite, Campus
Virchow Clinic, Berlin, Germany.
    BACKGROUND AND PURPOSE: The organic solvent dimethyl-sulfoxide (DMSO),
as a commonly used vehicle for nonadhesive liquid embolics, is not devoid of
local angiotoxic effects. We compared microvascular toxicities of
superselective infusions of DMSO with potentially more compatible solvents
in swine rete mirabile. METHODS: Fourteen swine underwent angiography for
superselective catheterization of 28 arteries of the rete while
electrocardiography and intra-arterial pressure were continuously monitored.
The investigated solvents were DMSO, dimethyl isosorbide (DMI), ethyl
lactate, glycofurol 75, N-methyl pyrrolidone (NMP), and solketal. Control
infusion of saline ruled out catheter induced vasospasm in all cases. Each
artery of the rete was infused only once with 0.8 mL of one of the solvents
over 60 seconds. Acute angiographic and hemodynamic consequences were
evaluated. Blood samples were assessed for signs of intravascular hemolysis.
Brains and retia were harvested for gross and histopathologic investigation.
RESULTS: On the basis of the angiographic data, DMSO induced the most
pronounced vasospasm with the longest recovery period of all solvents
investigated. Ethyl lactate, glycofurol 75, and solketal elicited less
severe vasospasms and accordingly resolved much more quickly. DMI and NMP
induced only minimal vasospasms with comparably short duration. No solvent
caused significant hemodynamic alterations or hemolysis. Gross inspection of
brains showed no abnormalities, whereas histopathologic examination revealed
mostly nonspecific findings. One rete exposed to solketal displayed possible
causal histotoxic changes. CONCLUSION: DMI and NMP produced far less
vasospasm than DMSO. No changes in hemodynamic or hemolytic parameters and
no histopathologic findings were observed with infusion of these solvents.
PMID: 17032862

PDA J Pharm Sci Technol. 2001 Jan-Feb;55(1):16-23.
Comparative hemolytic activity of undiluted organic water-miscible solvents
for intravenous and intra-arterial injection.
    Mottu F, Stelling MJ, R fenacht DA, Doelker E. School of Pharmacy,
University of Geneva, Switzerland.
    In humans, nonaqueous solvents are administered intravascularly in two
kinds of situations. They have been used in subcutaneous or intramuscular
pharmaceutical formulations to dissolve water-insoluble drugs. The need for
these vehicles had increased in recent years, since the drug development
process has yielded many poorly water-soluble drugs. The use of
water-miscible nonaqueous solvents in therefore one of the approaches for
administering these products as reference solutions useful in formulation
bioequivalence studies. The intravascular use of organic solvents has also
gained importance owing to a new approach for the treatment of cerebral
malformations using precipitating polymers dissolved in water-miscible
organic solvents. At present, the solvent most commonly used for the liquid
embolics to solubilize the polymers is dimethyl sulfoxide, which exhibits
some local and hemodynamic toxicities. In order to find new, less toxic
vehicles for pharmaceutical formulations for the intravenous and
intra-arterial routes and for embolic materials, 13 water-miscible organic
solvents currently used (diluted with water) for pharmaceutical
applications, were evaluated in this study. Their hemolytic activity and the
morphological changes induced when mixed with blood (1:99, 5:95, 10:90
solvent:blood) were estimated in vitro. From these data, the selected
organic solvents could be subdivided into four groups depending on their
hemolytic activity: very highly hemolytic solvents (ethyl lactate, dimethyl
sulfoxide), highly hemolytic solvents (polyethylene glycol 200, acetone),
moderately hemolytic solvents (tetrahydrofurfuryl alcohol,
N-methyl-2-pyrrolidone, glycerol formal, ethanol, Solketal, glycofurol) and
solvents with low hemolytic activity (propylene glycol, dimethyl isosorbide,
diglyme).
PMID: 11212416

[A limitation regarding the use of  dimethyl isosorbide in vitrification
solutions is a diffusion rate slightly lower than propylene glycol.]

Eur J Pharm Biopharm. 1998 Nov;46(3):265-71.
Codiffusion of propylene glycol and dimethyl isosorbide in hairless mouse
skin.
    Squillante E, Needham T, Maniar A, Kislalioglu S, Zia H. Department of
Applied Pharmaceutics, University of Rhode Island, Kingston, RI 02881, USA.
    The in vitro percutaneous fluxes of propylene glycol (PG), cis-oleic
acid (OA) and dimethyl isosorbide (DI) were determined and their effect on
nifedipine (N) flux and lag time evaluated. PG, OA and DI flux through
hairless mouse (HM) skin was measured in vitro by beta-scintigraphy and N
permeation was measured by HPLC under finite and infinite dose conditions.
Evaluation of each of the solvents separately showed that pure DI possessed
the inherent ability to traverse the skin (12% in 24 h). For the tested
formulation after 24 h, 57% of the PG and 40% of the DI had permeated across
the skin with nearly linear permeation between 4 and 18 h and the relative
order of permeation was PG > DI > N. DI permeation was further aided in the
presence of PG and OA. N flux was dependent on concomitant solvent
permeation. Over a 24-h test period a dose dependent response was observed
for N, with 4.9-15.6 mg of N delivered from the lowest and highest doses,
respectively, and the highest dose yielding zero-order flux of 146 (g/h per
cm2). Copyright 1998 Elsevier Science B.V.
PMID: 9885297

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